US20080234305A1 - Novel Tetrahydropyridine Derivatives - Google Patents

Novel Tetrahydropyridine Derivatives Download PDF

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US20080234305A1
US20080234305A1 US10/575,348 US57534804A US2008234305A1 US 20080234305 A1 US20080234305 A1 US 20080234305A1 US 57534804 A US57534804 A US 57534804A US 2008234305 A1 US2008234305 A1 US 2008234305A1
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phenyl
chloro
propyl
difluorophenoxy
amide
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Olivier Bezencon
Daniel Bur
Walter Fischli
Lubos Remen
Sylvia Richard-Bildstein
Thierry Sifferlen
Thomas Weller
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Assigned to ACTELION PHARMACEUTICALS LTD. reassignment ACTELION PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEZENCON, OLIVER, BUR, DANIEL, FISCHLI, WALTER, REMEN, LUBOS, RICHARD-BILDSTEIN, SYLVIA, SIFFERLEN, THIERRY, WELLER, THOMAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Definitions

  • the invention relates to novel five-membered heteroaryl derivatives of the general formula (I).
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I) and especially their use as renin inhibitors in cardiovascular events and renal insufficiency.
  • renin-angiotensin II the biologically active angiotensin II (Ang II) is generated by a two-step mechanism.
  • the highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE).
  • Ang II is known to work on at least two receptor subtypes called AT 1 and AT 2 . Whereas AT 1 seems to transmit most of the known functions of Ang II, the role of AT 2 is still unknown.
  • ACE inhibitors and AT 1 blockers have been accepted to treat hypertension (Waeber B. et al., “The renin-angiotensin system: role in experimental and human hypertension”, in Berkenhager W. H., Reid J. L. (eds): Hypertension , Amsterdam, Elsevier Science Publishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S).
  • ACE inhibitors are used for renal protection (Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J. A.
  • renin inhibitors The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645).
  • the only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin.
  • ACE can also cleave bradykinin besides Ang I and can be by-passed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 11, 1155). In patients inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Konili Z. H.
  • ACE inhibitors do not inhibit Chymase. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors.
  • Blockade of the AT 1 receptor e.g. by losartan
  • AT 2 AT-receptor subtypes
  • renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and AT 1 blockers with regard to efficacy in blocking the RAS and in safety aspects.
  • renin inhibitors with good oral bioavailability and long duration of action are required.
  • the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; Patent Application WO97/09311; Märki H. P. et al., II Farmaco, 2001, 56, 21).
  • the development status of these compounds is not known.
  • the present invention relates to the identification of renin inhibitors of a non-peptidic nature and of low molecular weight. Described are orally active renin inhibitors of long duration of action, which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically alter local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. So, the present invention describes these non-peptidic renin inhibitors.
  • lower alkyl alone or in combination with other groups, means saturated, straight and branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms that can be optionally substituted by halogens.
  • Examples of lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl.
  • the methyl, ethyl and isopropyl groups are preferred.
  • lower alkoxy refers to a R—O group, wherein R is a lower alkyl.
  • Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.
  • lower alkenyl alone or in combination with other groups, means straight and branched chain groups comprising an olefinic bond and two to seven carbon atoms, preferably two to four carbon atoms, that can be optionally substituted by halogens.
  • Examples of lower alkenyl are vinyl, propenyl or butenyl.
  • lower alkinyl alone or in combination with other groups, means straight and branched chain groups comprising a triple bond and two to seven carbon atoms, preferably two to four carbon atoms that can be optionally substituted by halogens.
  • Examples of lower alkinyl are ethinyl, propinyl or butinyl.
  • lower alkylene alone or in combination with other groups, means straight and branched divalent chain groups with one to seven carbon atoms, preferably one to four carbon atoms that can be optionally substituted by halogens.
  • Examples of lower alkylene are methylene, ethylene, propylene or butylene.
  • lower alkenylene alone or in combination with other groups, means straight and branched divalent chain groups comprising an olefinic bond and two to seven carbon atoms, preferably two to four carbon atoms, that can be optionally substituted by halogens.
  • Examples of lower alkenylene are vinylene, propenylene and butenylene.
  • lower alkylenedioxy refers to a lower alkylene substituted at each end by an oxygen atom.
  • Examples of lower alkylenedioxy groups are preferably methylenedioxy and ethylenedioxy.
  • lower alkylenoxy refers to a lower alkylene substituted at one end by an oxygen atom.
  • Examples of lower alkylenoxy groups are preferably methylenoxy, ethylenoxy and propylenoxy.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
  • cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which can be optionally mono-, di-, or trisubstituted independently by lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkylenoxy, lower alkylenedioxy, hydroxy, halogen, —CF 3 , —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 S(O) 2 R 2 , —C(O)NR 1 R 2 , lower alkylcarbonyl, —COOR 1 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 .
  • the cyclopropyl group is a preferred group, whereby
  • aryl alone or in combination, relates to the phenyl, the naphthyl or the indanyl group, preferably the phenyl group, which can be optionally mono-, di-, tri-, tetra- or penta-substituted independently by lower alkyl, lower alkenyl, lower alkinyl, lower alkenylene or lower alkylene forming with the aryl ring a five- or six-membered ring, lower alkoxy, lower alkylenedioxy, lower alkylenoxy, hydroxy, hydroxy-lower alkyl, halogen, cyano, —CF 3 , —OCF 3 , —NR 1 R 2 , -lower alkyl —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 S(O) 2 R 2 , —C(O)NR 1 R 2 , —NO 2 , lower alkylcarbonyl, —COOR 1
  • aryl means for example a phenyl group which is mono-, di-, tri-, tetra- or penta-substituted independently by fluorine or chlorine, such as for example: 2-chloro-3,6-difluoro-phenyl.
  • aryl means for example a phenyl group which is mono-, di-, tri-, tetra- or pentasubstituted independently by fluorine or chlorine, such as for example: 2,3-dichloro-phenyl.
  • aryloxy refers to an Ar—O group, wherein Ar is an aryl.
  • An example of aryloxy groups is phenoxy.
  • heterocyclyl alone or in combination, means saturated or unsaturated (but not aromatic) five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings can be optionally substituted with lower alkyl, hydroxy, lower alkoxy and halogen.
  • the nitrogen atoms, if present, can be substituted by a —COOR 2 group, whereby R 2 has the meaning given in the Formula (I) below.
  • rings are piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.
  • heteroaryl alone or in combination, means six-membered aromatic rings containing one to four nitrogen atoms; benzofused six-membered aromatic rings containing one to three nitrogen atoms; five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom; benzofused five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom; five-membered aromatic rings containing one oxygen and one nitrogen atom and benzofused derivatives thereof; five-membered aromatic rings containing a sulfur and a nitrogen or an oxygen atom and benzofused derivatives thereof; five-membered aromatic rings containing two nitrogen atoms and benzofused derivatives thereof; five-membered aromatic rings containing three nitrogen atoms and benzofused derivatives thereof, or a tetrazolyl ring.
  • Examples of such ring systems are furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl, quinoxalinyl.
  • Such rings may be adequately substituted with lower alkyl, lower alkenyl, lower alkinyl, lower alkylene, lower alkenylene, lower alkylenedioxy, lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen, cyano, —CF 3 , —OCF 3 , —NR 1 R 2 , —NR 1 R 2 — lower alkyl, —N(R 1 )COR 1 , —N(R 1 )SO 2 R 1 , —CONR 1 R 2 , —NO 2 , lower alkylcarbonyl, —COOR 1 , —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —SO 2 NR 1 R 2 , whereby R 1 and R 2 have the meaning given in formula (I) below, another aryl, another heteroaryl or another heterocyclyl and the like.
  • the heteroaryl may additionally be substituted with a group hydroxyl-lower alkylene-oxy, wherein lower alkylene is as defined above (preferred example for lower alkylene is ethylene).
  • heteroaryl means for example pyridinyl thiazoyl, oxazoyl, and isoxazoyl.
  • heteroaryl means for example isoxazoyl, pyrrazoyl.
  • heteroaryl means for example pyridinyl substituted with lower alkyl, hydroxyl-lower alkylene-oxy, and lower alkoxy, such as 2-methoxy-3-methylpyridin-4-yl.
  • a preferred example is 2-(3-hydroxypropoxy)-3-methylpyridin-4-ylmethyl.
  • heteroaryloxy refers to a Het-O group, wherein Het is a heteroaryl.
  • heteroaryl-lower alkyl means that a heteroaryl as define above is attached to a lower alkyl group as defined above.
  • An example is pyridinyl-methyl.
  • Further examples are the following heteroaryl groups attached to a methyl group: furanyl, thiophenyl, pyrrolyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl and quinoxalinyl.
  • aryl-lower alkyl means that an aryl as define above is attached to a lower alkyl group as defined above.
  • An example is phenyl-methyl (benzyl).
  • Further examples are the following aryl groups attached to a methyl group: naphthyl and indanyl.
  • cycloalkyl-lower alkyl means that a cycloalkyl as define above is attached to a lower alkyl group as defined above.
  • An example is cyclopropyl-methyl.
  • Further examples are the following cycloalkyl groups attached to a methyl group: cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula (I) is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula (I) is
  • the compounds of the general formula (I) can contain one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and the meso-form and pharmaceutically acceptable salts thereof.
  • Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC or crystallization.
  • a first aspect of the invention consists in novel tetrahydropyridine derivatives of the general formula (I).
  • the tetrahydropyridine derivatives of the general formula (I) as described above also encompass optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and the meso-form; as well as pharmaceutically acceptable salts, solvent complexes and morphological forms.
  • a group of preferred compounds of general formula (I) are those wherein X, Y, V, W and U are as defined in general formula (I) and wherein T represents —CONR 1 —; Q represents a lower alkylene; M represents hydrogen, aryl or heteroaryl.
  • Another group of preferred compounds of general formula (I) are those wherein X, Y, W, T, Q and M are as defined in general formula (I), V represents —CH 2 CH 2 O—; —CH 2 CH 2 CH 2 O—; —OCH 2 CH 2 O— or —CH 2 CH 2 CH 2 OCH 2 O— and U is as above-defined in general formula (I).
  • a group of more preferred compounds of general formula (I) are those wherein X, Y, V, U, T, Q and M are as defined in general formula (I) and W represents a phenyl substituted in 4-position with V.
  • Another group of particularly more preferred compounds of general formula (I) are those wherein W, V, U, T, Q, and M are as defined in general formula (I) and X and Y together may form a cyclopropyl group.
  • a and B independently represent —O—.
  • R 1 and R 2 independently represent cycloalkyl, such as cyclopropyl.
  • the group V as defined above such as -A-(CH 2 ) s — is integrated into a compound of formula I in that A is attached to U and the alkylene part of -A-(CH 2 ) s — is attached to W.
  • p represents the integer 1.
  • r represents the integer 3 or 4.
  • s represents the integer 2 or 3.
  • t represents the integer 1 or 2.
  • u represents the integer 1 or 2.
  • v represents the integer to 2 or 3. In a further preferred embodiment v represents the integer 2.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system, which method comprises administrating a compound as defined above to a human being or animal.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases, which are associated with a dysregulation of the renin-angiotensin system as well as for the treatment of the above-mentioned diseases.
  • the invention also relates to the use of compounds of formula (I) for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases.
  • a further aspect of the present invention is related to a pharmaceutical composition containing at least one compound according to general formula (I) and pharmaceutically acceptable carrier materials or adjuvants.
  • This pharmaceutical composition may be used for the treatment or prophylaxis of the above-mentioned disorders; as well as for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases.
  • Derivatives of formula (I) or the above-mentioned pharmaceutical compositions are also of use in combination with other pharmacologically active compounds comprising ACE-inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases.
  • this amount is comprised between 2 mg and 1000 mg per day.
  • this amount is comprised between 1 mg and 500 mg per day.
  • this amount is comprised between 5 mg and 200 mg per day.
  • Compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical compositions containing at least one compound of formula (I) and pharmaceutically acceptable inert carrier material or adjuvants.
  • These pharmaceutical compositions can be used for enteral, parenteral, or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula (I) and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injections are, for example, water, alcohols, polyols, glycerols and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case.
  • Another aspect of the invention is related to a process for the preparation of a pharmaceutical composition comprising a derivative of the general formula (I).
  • one or more active ingredients of the general formula (I) are mixing with inert excipients in a manner known per se.
  • the compounds of general formula I can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods.
  • the compounds of general formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
  • the tetrahydropyridine derivatives exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • Precursors are compounds, which were prepared as key intermediates and/or building blocks and are suitable for further transformations in parallel chemistry.
  • a compound of type A is prepared from a known 4-oxopiperidine derivative (Scheme 1), whereas PG represents a suitable protecting group. Subsequent acylation leads to a compound of type B (Majewski, M; et al.; J. Org. Chem., 1995, 60, 5825), whereas R a is a suitable ester (e.g. ethyl, methyl and benzyl).
  • a compound of type D can be transprotected to a compound of type E, then coupled to a phenol or aromatic alcohol using a Mitsunobu reaction, leading to derivatives of type F wherein V and U have the meaning given in general formula I as above-mentioned.
  • the ester F is optionally cleaved by any suitable method to lead to precursor G (Scheme 3).
  • a compound of type D can be reduced to a compound of type M that can be then oxidized to a compound of type N (Scheme 4).
  • Aldehyde N can then be transformed to a compound of type O by reductive amination, which can be acylated to a derivative of type Q′ wherein Q and M have the meaning given in general formula (I) above.
  • compounds of type M can be then acylated following standard procedures to esters or carbamates of type P.
  • Preparation of a monofluorated derivative can start from the commercially available N-protected piperidin-4-one S (Scheme 5). Fluorination by a reagent delivering an F + -synthon, like DAST or Selectfluor®, can lead to a derivatives of type S′. Acylation with nitriloacetic acid methyl ester for instance can lead to derivatives of type T′. Then a similar chemistry can be used as described here above (Schemes 2-4).
  • a difluorinated derivative of type T′′ must be prepared through a different way (Scheme 6). Condensation of N-benzyl- ⁇ -alanine ethyl ester with formaldehyde and benzotriazol yields compound V. Compound W is obtained following a reaction with a Reformasky type reagent. Then a Dieckmann cyclization leads to compound T′′, which is structurally similar to compound C (Scheme 2).
  • a compound of type G can be coupled to the amine to yield amides of type L wherein V, U and M have the meaning given in general formula (I) above. Removal of the N-protecting group (PG) leads to the final compounds of type R wherein V, U, Q and M have the meaning given in general formula (I) above (Scheme 8).
  • the starting material was dissolved in CH 2 Cl 2 (10 mL/g of starting material) and the sol. was cooled to 0° C. 4M HCl in dioxane (same volume as CH 2 Cl 2 ) was added and the reaction mixture was left for 90 min at rt. The solvents were removed under reduced pressure. Purification of the residue by HPLC led to the desired compound.
  • 2-Chloro-N-phenylisonicotinamide To the sol. of 2-chloroisonicotinoyl chloride (Anderson, W. K., Dean, D. C., Endo, T., J. Med. Chem., 1990, 33, 1667, 10 g, 56.8 mmol) in 1,2-dichloroethane (100 mL) was added at 0° C. a sol. of aniline (5.70 mL, 62.5 mmol) and DIPEA (10.2 ml, 59.6 mmol) in 1,2-dichloroethane (10 ml) during ca. 30 min. The reaction was stirred at 0° C. for ca.
  • N-Benzyl- ⁇ -alanine ethyl ester (2.07 g, 10 mmol), followed by 37% aqueous formaldehyde (0.99 mL, 12 mmol) were added to a solution of benzotriazole (1.19 g, 10 mmol) in MeOH (7 mL). The solution was stirred overnight, and then the solvent was evaporated under reduced pressure. Purification of the residue by FC (EtOAc/heptane 3:7) yielded the title compound (3.24 g, 96%).
  • the enzymatic in vitro assay was performed in 384-well polypropylene plates (Nunc).
  • the assay buffer consisted of 10 mM PBS (Gibco BRL) including 1 mM EDTA and 0.1% BSA.
  • the incubates were composed of 50 ⁇ L per well of an enzyme mix and 2.5 ⁇ L of renin inhibitors in DMSO.
  • the enzyme mix was premixed at 4° C. and consists of the following components:
  • the accumulated Ang I was detected by an enzyme immunoassay (EIA) in 384-well plates (Nunc). 5 ⁇ L of the incubates or standards were transferred to immuno plates which were previously coated with a covalent complex of Ang I and bovine serum albumin (Ang I-BSA). 75 ⁇ L of Ang I-antibodies in assay buffer above including 0.01% Tween 20 were added and a primary incubation made at 4° C. overnight. The plates were washed 3 times with PBS including 0.01% Tween 20, and then incubated for 2 h at rt with an antirabbit-peroxidase coupled antibody (WA 934, Amersham).
  • EIA enzyme immunoassay
  • the peroxidase substrate ABTS (2.2′-azino-di-(3-ethyl-benzthiazolinsulfonate), was added and the plates incubated for 60 min at rt. After stopping the reaction with 0.1 M citric acid pH 4.3 the plate was evaluated in a microplate reader at 405 nm. The percentage of inhibition was calculated of each concentration point and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50% (IC 50 ).

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US20090062342A1 (en) * 2006-03-08 2009-03-05 Actelion Pharmaceuticals Ltd. Amines
US20090306123A1 (en) * 2004-08-25 2009-12-10 Olivier Bezencon Bicyclononene derivaties

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WO2007009250A1 (en) * 2005-07-22 2007-01-25 Merck Frosst Canada Ltd. Renin inhibitors
EP2420491B1 (en) 2005-12-30 2013-07-03 Novartis AG 3 , 5-substitued piperidine compounds as renin inhibitors
KR20080100382A (ko) * 2006-03-03 2008-11-17 액테리온 파마슈티칼 리미티드 레닌 저해제로서의 1차 아민
EP1908471A1 (en) * 2006-10-04 2008-04-09 Speedel Experimenta AG Tetrahydropyridines as renin inhibitors
WO2008141462A1 (en) 2007-05-24 2008-11-27 Merck Frosst Canada Ltd. Novel case of renin inhibitors
BRPI0813900A2 (pt) 2007-06-25 2014-12-30 Novartis Ag Derivados de n5-(2-etoxietil)-n3-(2-piridinil)-3,5-piperidinodicarboxa mida para uso como inibidores de renina
AU2008288648A1 (en) 2007-08-20 2009-02-26 Merck Frosst Canada Ltd. Renin inhibitors
JP5383699B2 (ja) 2007-12-05 2014-01-08 ビーエーエスエフ ソシエタス・ヨーロピア ピリジルメチル−スルホンアミド化合物
RU2010137300A (ru) 2008-02-22 2012-03-27 Ф. Хоффманн-Ля Рош Аг (Ch) Модуляторы бета-амилоида
KR20130029116A (ko) 2008-05-05 2013-03-21 머크 샤프 앤드 돔 리미티드 레닌 억제제로서의 3,4-치환된 피페리딘 유도체
BRPI0920651A2 (pt) 2008-10-09 2016-01-12 Hoffmann La Roche moduladores para amiloide beta
JP5378532B2 (ja) 2008-11-10 2013-12-25 エフ．ホフマン−ラ ロシュ アーゲー 複素環γ−セクレターゼモジュレーター
CA2749837C (en) 2009-01-21 2017-07-11 Rigel Pharmaceuticals, Inc. Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases
CN101696187B (zh) * 2009-09-30 2011-09-07 徐州工业职业技术学院 N-取代基-1,2,3,6-四氢吡啶的合成方法
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US9187435B2 (en) 2010-11-17 2015-11-17 Actelion Pharmaceuticals Ltd. Bridged Spiro[2.4]heptane ester derivatives
MA37618B1 (fr) 2012-05-16 2017-08-31 Actelion Pharmaceuticals Ltd Dérivés pontés fluorés de spiro[2.4]heptane en tant qu'agonistes de récepteur alx

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US20090062342A1 (en) * 2006-03-08 2009-03-05 Actelion Pharmaceuticals Ltd. Amines

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